Findings further support paramagnetic rim lesions as MS biomarker

Paramagnetic rim lesions (PRL), a manifestation of chronic white matter inflammation seen on MRI, were associated with elevated levels of serum neurofilament light chain (NfL), a marker of axonal damage, in people with multiple sclerosis (MS), a cross-sectional study found.

MS patients with two or more paramagnetic rim lesions had higher age-adjusted NfL percentiles than those with one or no PRL (median 91 and 68, respectively, P<0.001), reported Cristina Granziera, MD, PhD, of the University of Basel in Switzerland, and co-authors.

People with two or more paramagnetic rim lesions showed worse function (higher score) on the Multiple Sclerosis Severity Score (MSSS) compared with those who had zero or one lesion (median 4.3 versus 2.4, respectively, P=0.003).

“The association between PRL and serum NfL was strong and independent from other factors known to influence serum NfL levels,” Granziera and colleagues wrote in Neurology. “Hence, we postulate that PRL may be a substantial driver of neuro-axonal damage and clinical disability in patients without clinical or radiological signs of acute inflammation.”

“This is a concept of key importance and further supports the role of PRL as a biomarker for patient stratification and treatment outcome in future clinical trials,” they added.

The researchers studied 118 MS patients (median age 45) with no gadolinium-enhancing lesions (which signify acute inflammation) within 2 months of the study MRI. Participants had either relapsing (73%) or progressive (27%) forms of MS. Data were collected from December 2017 to September 2019.

Overall, 59% of participants had one or more PRL, 36% had two or more PRL, and 25% had 4 or more PRL. Those with two or more PRL had a mean NfL level 16 percentile-points higher than those with zero or one lesion (βadd 16.3, 95% CI 4.6–28.0, P<0.01). No other covariate, including MS subtype, disease modifying therapy, disability score, or T2-lesion load, had an independent effect on NfL levels.

“This study is important because it confirms that paramagnetic rim lesions represent chronic active lesions with acute axonal injury, and, for the first time, combines and relates the visualization of paramagnetic rim lesions to serum NfL quantifications in-vivo,” noted Paolo Preziosa, MD, PhD, and Menno Schoonheim, MSc, PhD, both of the San Raffaele Scientific Institute in Milan, in an accompanying editorial.

“In addition to supporting the clinical relevance of paramagnetic rim lesions, this study also indicates that serum NfL levels could become a useful biomarker to quantify chronic active lesion-driven neurodegeneration that may also occur independently from overt clinical or radiological disease activity,” they added. “However, MRI protocols required to identify paramagnetic rim lesions still require standardization before clinical implementation is feasible.”

Prior work has shown NfL levels increase with acute inflammation marked by gadolinium-enhancing lesions in MS, and correlate with the burden of these findings on MRI, but whether NfL tracks chronic inflammation as measured by PRL was not known.

Acute phase MS lesions include an infiltrate of activated microglia, macrophages, and lymphocytes and show demyelination and axonal damage. Some lesions become inactive but half or more show ongoing inflammation and are called chronic active lesions with a hypocellular core, iron-laden microglia and macrophages at their rim, and ongoing inflammatory damage.

“Of note, chronic active lesions lack substantially abnormal blood-brain barrier permeability that typically characterize acute lesions, thus reflecting a more compartmentalized pathological process which is more difficult to visualize on MRI,” the editorialists wrote.

In the present study, Granziera and colleagues also examined 20 autopsy samples from MS patients, including 19 people who had progressive MS, with mean age of 52.

“Our postmortem evaluation shows that the histological correlates of PRL—chronic active and smoldering lesions—exhibit pronounced axon damage at the lesion edge, which colocalizes with chronic inflammatory cells,” the researchers observed. “Quantification of CD68+ activated microglia/macrophages and CD68+ phagocytes containing myelin-basic-protein-positive particles showed that chronic active and smoldering lesions fall on a spectrum of inflammatory demyelinating activity at the lesion edge and hypocellular core.”

“Further efforts are necessary to evaluate the longitudinal evolution of paramagnetic rim lesions and serum NfL levels, especially in the context of initiating and/or escalating treatment, to confirm their clinical relevance and their usefulness for treatment monitoring,” the editorialists wrote.

Limitations of the study include those inherent to cross-sectional design. In addition, there was delay of several months in a few cases between MRI and serum NfL measurements; the chronic inflammatory status presumed to link PRL and NfL levels may have changed in that interval (median interval was 15 days).

  1. Paramagnetic rim lesions, a manifestation of chronic white matter inflammation seen on MRI, were associated with elevated levels of serum neurofilament light chain (NfL), a marker of axonal injury, in people with multiple sclerosis.

  2. Paramagnetic rim lesions may be a substantial driver of neuro-axonal damage in MS patients without clinical or radiological signs of acute inflammation, the researchers suggested.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was partially supported by the NIH Intramural Research Program, the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie project TRABIT, and the CIBM Center for Biomedical Imaging.

Granziera is supported by the Swiss National Science Foundation, the Stiftung zur Förderung der gastroenterologischen und all-gemeinen klinischen Forschung, and Eurostars Horizon 2020.

Schoonheim serves on the editorial board of Frontiers in Neurology, receives research support from the Dutch MS Research Foundation and Amsterdam Neuroscience, and has served as a consultant for or received research support and/or speaker honoraria from Atara Biotherapeutics, Biogen, Celgene, Genzyme, MedDay, and Merck. Preziosa received speaker honoraria from Biogen Idec, Novartis, Bristol Myers Squibb, Genzyme, and ExceMED. He is supported by a senior research fellowship Fondazione Italiana Sclerosi Multipla.

Cat ID: 36

Topic ID: 82,36,730,36,192,925